Therapeutic Potential of Saffron Extract in Mild Depression: A Study of Its Role on Anhedonia in Rats and Humans.

Drugs generally used in major depressive disorder are considered inappropriate for the more common milder forms. The efficacy of saffron extracts has been demonstrated in mild to moderate depression and in preclinical models of depression. However, evidence of saffron activity on reduced hedonic responsiveness and motivational anhedonia is limited. Since dopamine transmission dysfunctions are crucially involved in anhedonia and saffron seems to positively modulate dopamine release, we studied the potential antidepressant and anti-anhedonic effects of a standardized formulation of saffron extract in preclinical models of anhedonia-like behaviors, and patients diagnosed with unipolar or bipolar depression. We tested saffron activity in a rat model of stress-induced motivational anhedonia using sucrose self-administration protocols and investigated the molecular underpinnings of this effect focusing on DARPP-32 phosphorylation pattern in response to a reinforcer and BDNF-TrkB signaling, in the nucleus accumbens and medial prefrontal cortex. In parallel, with a pilot double-blind placebo-controlled study we investigated whether saffron add-on therapy reduced symptoms of depression and anhedonia, measured by the Montgomery-Åsberg Depression Rating Scale. Repeated saffron administration restored motivation and reactivity to reward-associated cues in anhedonic rats, likely modulating dopaminergic transmission and BDNF-TrkB signaling. In depressed patients, an 8-week saffron add-on therapy induced a global improvement in depressive symptoms and a significant reduction in anhedonia. The study supports a pro-motivational effect of saffron and suggests a potentially useful saffron-based augmentation strategy in anhedonic patients, albeit with limitations due to small sample size and short trial duration.